Cancer and AIDS represent complex diseases that are controlled by the environment and by genetic factors of the host. A number of inherited cancer syndromes have been described, and the genes responsible for several of these genetic diseases have been identified. Genetically inherited cancers follow the tumor suppressor model, whereby the loss of function of a gene important to normal growth control leads to malignancy. Tumor suppressor genes also play a role in sporadic malignancies. In HIV- related disease, extensive heterogeneity in the response to the virus suggests that genetic factors in the host play a role in the disease. Analysis of siblings that have both become infected suggests that there are modifying or restriction genes. Genetic analysis of each of these diseases requires the availability of genetic markers in genes that may be candidate genes. Although over 5,000 human restriction fragment length polymorphisms have been described, only 1,500 are in coding genes. This represents a small proportion of the 50-100,000 genes. We have employed standard approaches as well as new methods to characterize polymorphisms in biologically important human genes. (1) The single-stranded conforma- tion polymorphism method has been used to identify polymorphisms in non- coding portions of genes. (2) Highly polymorphic microsatellite loci in and near genes have allowed detailed genetic maps of important regions to be generated. (3) Sequences surrounding Not I restriction sites in chromosome 3 have been used as markers for expressed sequences, and to generate genetic markers. Polymorphisms have been described in the IKB gene (an inhibitor of a transcription factor that acts on HIV) and the immunoglobulin heavy chain genes. These markers will be analyzed in a cohort of HIV-infected individuals. Over 20 loci that represent expressed sequences have been mapped on chromosome 3, a chromosome involved in cytogenetic abnormalities in a number of malignancies. These expressed sequence markers will be employed in identifying putative tumor suppressor loci. A fine structure genetic map of the nevoid basal cell carcinoma syndrome region has been constructed.